Comparison of diagnostic algorithms used in guidelines on nutritional anaemias in adults

Margaretha G. M. Roemer; Wendy P. J. den Elzen; Rosalinde K. E. Poortvliet; Jacobijn Gussekloo; Steef Kurstjens; Bauke A. de Boer; Anne Margreet de Jong

doi:10.1371/journal.pone.0333688

Peer Review History

Original SubmissionJanuary 6, 2025
27 May 2025 Decision Letter - Elizabeth Mayne, Editor PONE-D-25-00163Diagnostic algorithms in guidelines on anaemia: a systematic reviewPLOS ONE Dear Dr. De Jong, Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process. ============================== The reviewers suggested some minor amendments including some grammatical changes and in addition a few references to support the ferritin analysis. I also feel that the proposed title change (review of nutritional anaemias) is a good suggestion. ============================== Please submit your revised manuscript by Jul 11 2025 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org . 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Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here. Reviewer #1: Yes Reviewer #2: Yes ****** 5. Review Comments to the Author Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters) Reviewer #1: Thank you for the opportunity to review your manuscript that investigates similarities and differences in diagnostic algorithms of clinical treatment guidelines of nutritional anaemia in adult patients. Major observations: 1. While many of the PRISMA 2020 checklist items were followed, I consider this manuscript to represent a narrative and thematic synthesis describing and comparing the guidelines and their recommendations. The quality of evidence and strength of recommendations contained in each clinical practice guideline were not evaluated using a recognised approach e.g., a rapid (iCAHE) or a complex instrument (the GRADE, AGREE II and AGREE-REX). In this respect I consider the methodology to fall short of a complete systematic review. I question the application of the scoring system used in the manuscript to rate the quality of the guidelines (p.5 3rd paragraph, 2nd sentence) as a suitable alternative. Table 1 shows three CPGs (8[2022], 14[2019], and 20[2018]) with similar diagnostic algorithms for iron deficiency yet variable evidence. Minor observations: 1. I believe the title of the manuscript should be amended to reflect the focus of the work: e.g., Diagnostic algorithms in guidelines on nutritional anaemias in adults. 2. While Qatar’s health care system is a leader in the Gulf Cooperation Council, is it really similar to the healthcare systems of e.g., Western European countries in this study? Developing vs. developed health care system? As an example, in 2020 Qatar’s health care spending has exceeded its European counterparts but it was predominantly toward secondary care (70-75%), with ~20-25% for primary care and <5% for self-care. The comparative breakdown for the Netherlands was ~45%, ~45%, and ~10% for secondary, primary, and self-care, respectively. 3. p.4. 2nd paragraph 2nd last sentence: amend under- of overtreatment to under- or overtreatment 4. p.5 3rd paragraph 1st and 3rd sentence: repetitive: To ensure effective and standardised care, anaemia guidelines have been developed. Adhering to established clinical guidelines is advised to ensure effective and standardised care. Suggest consolidation. 5. p.5 3rd paragraph 4th sentence: I am unsure how physiological needs vary by ethnicity. Reconsider or substantiate. 6. References should be extensively reviewed to comply with the journal’s author guideline. In particular; 1. Use the Vancouver referencing style and, for consistency, restrict authors to the first six followed by et al. and 2. Review referencing style of internet resources. Some of the listed URLs are stale. 7. Abbreviations used in the tables should be explained in the caption e.g., <n; a=" " etc.=" " n=" ">8. The ferritin cut-off of reference 9 in Table 2 appears erroneous.</n;> Reviewer #2: This is a highly relevant and useful article which is well-written. Some minor grammatical edits are required, and additional suggested references are provided to include important pre-analytical factors affecting serum ferritin levels which are not widely recognized and can lead to diagnostic confusion. ****** 6. PLOS authors have the option to publish the peer review history of their article (what does this mean? ). If published, this will include your full peer review and any attached files. If you choose “no”, your identity will remain anonymous but your review may still be made public. Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy . Reviewer #1: No Reviewer #2: No ******** [NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.] While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/ . PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org . Please note that Supporting Information files do not need this step. Attachments Attachment Submitted filename: PONE-D-25-00163 (2)PLOSOneAnaemia_JJO.pdf https://doi.org/10.1371/journal.pone.0333688.r001
Revision 1
10 Jul 2025 Author Response Comments of academic editor The reviewers suggested some minor amendments including some grammatical changes and in addition a few references to support the ferritin analysis. I also feel that the proposed title change (review of nutritional anaemias) is a good suggestion. Thank you for the evaluation of our manuscript. We agree with the minor amendments and proposed title change and have adjusted the manuscript accordingly. Review comments to the Author Reviewer #1: Thank you for the opportunity to review your manuscript that investigates similarities and differences in diagnostic algorithms of clinical treatment guidelines of nutritional anaemia in adult patients. Major observations: 1. While many of the PRISMA 2020 checklist items were followed, I consider this manuscript to represent a narrative and thematic synthesis describing and comparing the guidelines and their recommendations. The quality of evidence and strength of recommendations contained in each clinical practice guideline were not evaluated using a recognised approach e.g., a rapid (iCAHE) or a complex instrument (the GRADE, AGREE II and AGREE-REX). In this respect I consider the methodology to fall short of a complete systematic review. I question the application of the scoring system used in the manuscript to rate the quality of the guidelines (p.5 3rd paragraph, 2nd sentence) as a suitable alternative. Table 1 shows three CPGs (8[2022], 14[2019], and 20[2018]) with similar diagnostic algorithms for iron deficiency yet variable evidence. We acknowledge the lack of a recognized grading approach for the different guidelines. However, it is important to note that we did not evaluate guidelines as a whole, but specifically focused on the laboratory parameters within the guidelines and the evidence that was used to support the different diagnostic algorithms. Consequently, the same guideline may have a different quality for the different nutritional anaemias, e.g. iron deficiency anaemia (evidence = 2) and vitamin B12/folate deficiency anaemia (evidence = 3) in the Dutch anaemia guideline. Similarly, even though a similar diagnostic algorithm is used in different guidelines, the evidence supporting this algorithm may differ. To clarify this, we changed the following sentence in the discussion on page 10, line 10: “Furthermore, a lot of variation was seen in the recommended diagnostic criteria, cut-off values and evidence underpinning the algorithms, even in the presence of similar diagnostic strategies.” We do agree that the wording in our title: “systematic review” may be misleading. Therefore, we removed this from the title and changed it to: “Comparison of diagnostic algorithms in guidelines on nutritional anaemias in adults”. Minor observations: 1. I believe the title of the manuscript should be amended to reflect the focus of the work: e.g., Diagnostic algorithms in guidelines on nutritional anaemias in adults. Thank you, we agree with this suggestion and have adjusted the title to: “Comparison of diagnostic algorithms in guidelines on nutritional anaemias in adults”. 2. While Qatar’s health care system is a leader in the Gulf Cooperation Council, is it really similar to the healthcare systems of e.g., Western European countries in this study? Developing vs. developed health care system? As an example, in 2020 Qatar’s health care spending has exceeded its European counterparts but it was predominantly toward secondary care (70-75%), with ~20-25% for primary care and <5% for self-care. The comparative breakdown for the Netherlands was ~45%, ~45%, and ~10% for secondary, primary, and self-care, respectively. There is certainly a difference between health care systems in different countries, but this is true even within Western European countries. For instance: in the Dutch health care system, the general practitioner acts as a gatekeeper for referral to medical specialists, while in the German health care system, patients have direct access to medical specialists. Qatar has consistently ranked among the top healthcare systems globally and we therefore believe that it is justified to include the Qatar anaemia guideline in this manuscript. 3. p.4. 2nd paragraph 2nd last sentence: amend under- of overtreatment to under- or overtreatment Done. 4. p.5 3rd paragraph 1st and 3rd sentence: repetitive: To ensure effective and standardised care, anaemia guidelines have been developed. Adhering to established clinical guidelines is advised to ensure effective and standardised care. Suggest consolidation. Thank you for pointing this out. We removed the second sentence. 5. p.5 3rd paragraph 4th sentence: I am unsure how physiological needs vary by ethnicity. Reconsider or substantiate. Agree. We reworded the sentence to: “For different physiological settings, including age, sex and pregnancy status or for specific patient groups, different guidelines for diagnosing anaemia have been developed.” 6. References should be extensively reviewed to comply with the journal’s author guideline. In particular; 1. Use the Vancouver referencing style and, for consistency, restrict authors to the first six followed by et al. and 2. Review referencing style of internet resources. Some of the listed URLs are stale. Done, see also point 6 of journal requirements. 7. Abbreviations used in the tables should be explained in the caption e.g., 8. The ferritin cut-off of reference 9 in Table 2 appears erroneous. We added a caption explaining the abbreviations to the tables. Reviewer #2: This is a highly relevant and useful article which is well-written. Some minor grammatical edits are required, and additional suggested references are provided to include important pre-analytical factors affecting serum ferritin levels which are not widely recognized and can lead to diagnostic confusion. We would like to thank the reviewer for her/his appreciative comments and for the effort invested in evaluating our work. We incorporated the suggested edits in the attached document. See specifics below: Edits in introduction: • grammar: to find the underlying cause • grammar: from ferritin only, to ferritin in various combinations... • suggest reword: affecting up to 25%... • add: red blood cells for the age and sex of the individual. • reword: The diagnosis of anaemia typically includes ... • suggest reword: physiological settings including age, sex, ... different guidelines for the diagnosis of anaemia have been developed. Edits in discussion: • the CBC • suggest delete. reword: we recommend including at least age and sex in the diagnostic algorithms • when the same sample is measured Edits in Table 1: • The (capitalise) • This international statement Hb specifically refers to the pre-operative management of anaemia. Please add this into the legend: * International consensus statement for pre-operative anaemia: Hb< 13 g/dl for both sexes. Edits in Figure 2: • use MCV as a supportive parameter only Furthermore, we incorporated the suggested references in the text. Specifically, on page 10, we added the reference to the ferritin cut-off study to the following sentence on line 30: “For iron deficiency anaemia, ferritin was included in all algorithms. However, the used cut-offs were variable, as has been previously described” In addition, we added the following sentence to the discussion, page 10, lines 35-38: “Furthermore, ferritin levels are affected by recent oral iron supplementation intake, coffee and other dietary factors. Therefore, it is recommended to fast and withhold supplements before measuring ferritin. Nonetheless, these factors are not emphasized in guidelines, and therefore this can lead to diagnostic confusion.” Journal requirements When submitting your revision, we need you to address these additional requirements. 1. Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. Done. 2. We note that your Data Availability Statement is currently as follows: [All relevant data are within the manuscript and its Supporting Information files.] Please confirm at this time whether or not your submission contains all raw data required to replicate the results of your study. Submission contains all data required. If there are ethical or legal restrictions on sharing a de-identified data set, please explain them in detail (e.g., data contain potentially sensitive information, data are owned by a third-party organization, etc.) and who has imposed them (e.g., an ethics committee). Please also provide contact information for a data access committee, ethics committee, or other institutional body to which data requests may be sent. If data are owned by a third party, please indicate how others may request data access. There are no ethical or legal restrictions. 3. Please include a copy of Table 1, 2 & 3 which you refer to in your text on page 7. Tables are placed in the manuscript file directly after the paragraph in which it is first cited, as described in the journal requirements. 4. Please include captions for your Supporting Information files at the end of your manuscript, and update any in-text citations to match accordingly. Please see our Supporting Information guidelines for more information: http://journals.plos.org/plosone/s/supporting-information. Supporting Information files are updated. Supporting information Supplementary Table 1. Exclusion table Supplementary Table 2. PRISMA abstract checklist Supplementary Table 3. PRISMA checklist 5. As required by our policy on Data Availability, please ensure your manuscript or supplementary information includes the following: A numbered table of all studies identified in the literature search, including those that were excluded from the analyses. For every excluded study, the table should list the reason(s) for exclusion. If any of the included studies are unpublished, include a link (URL) to the primary source or detailed information about how the content can be accessed. A table of all data extracted from the primary research sources for the systematic review and/or meta-analysis. The table must include the following information for each study: Name of data extractors and date of data extraction Confirmation that the study was eligible to be included in the review. All data extracted from each study for the reported systematic review and/or meta-analysis that would be needed to replicate your analyses. If data or supporting information were obtained from another source (e.g. correspondence with the author of the original research article), please provide the source of data and dates on which the data/information were obtained by your research group. We generated a table containing all identified guidelines in our database search. The dates of the search and date of assessment and consensus was added. Furthermore, we added the reason for exclusion. See Supplementary Table 1. If applicable for your analysis, a table showing the completed risk of bias and quality/certainty assessments for each study or outcome. Please ensure this is provided for each domain or parameter assessed. For example, if you used the Cochrane risk-of-bias tool for randomized trials, provide answers to each of the signalling questions for each study. If you used GRADE to assess certainty of evidence, provide judgements about each of the quality of evidence factor. This should be provided for each outcome. Not applicable An explanation of how missing data were handled. Not applicable This information can be included in the main text, supplementary information, or relevant data repository. Please note that providing these underlying data is a requirement for publication in this journal, and if these data are not provided your manuscript might be rejected. 6. Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice. Done, reference list was updated. Attachments Attachment Submitted filename: Response to Reviewers_guidelines on anaemia.docx https://doi.org/10.1371/journal.pone.0333688.r002
15 Aug 2025 Decision Letter - Elizabeth Mayne, Editor <div>PONE-D-25-00163R1Comparison of diagnostic algorithms in guidelines on nutritional anaemias in adultsPLOS ONE Dear Dr. De Jong, Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process. There are some minor grammatical and typographical changes which need to be done and one of the reviewers has requested a review of the one table. Please submit your revised manuscript by Sep 29 2025 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org . When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file. Please include the following items when submitting your revised manuscript: A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'. A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'. An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'. If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter. 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There is no requirement to cite these works unless the editor has indicated otherwise. Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice. [Note: HTML markup is below. Please do not edit.] Reviewers' comments: Reviewer's Responses to Questions Comments to the Author 1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation. Reviewer #1: All comments have been addressed Reviewer #2: (No Response) ******** 2. Is the manuscript technically sound, and do the data support the conclusions? The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented. Reviewer #1: Yes Reviewer #2: Yes ****** 3. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: N/A Reviewer #2: Yes ****** 4. Have the authors made all data underlying the findings in their manuscript fully available? The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified. Reviewer #1: Yes Reviewer #2: Yes ****** 5. Is the manuscript presented in an intelligible fashion and written in standard English? PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here. Reviewer #1: Yes Reviewer #2: Yes ****** 6. Review Comments to the Author Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters) Reviewer #1: All my comments have been adequately addressed. I have no more concerns on the content of the manuscript. Reviewer #2: I have further reviewed and provided detailed comments and edits on the manuscript in track changes. Whilst improved, the manuscript still requires further minor revisions and another round of review. ****** 7. PLOS authors have the option to publish the peer review history of their article (what does this mean? ). If published, this will include your full peer review and any attached files. If you choose “no”, your identity will remain anonymous but your review may still be made public. Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy . Reviewer #1: No Reviewer #2: No ******** [NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.] While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/ . PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. 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Revision 2
29 Aug 2025 Author Response Reviewer #1: All my comments have been adequately addressed. I have no more concerns on the content of the manuscript. Thank you for the evaluation of our revised manuscript. Reviewer #2: I have further reviewed and provided detailed comments and edits on the manuscript in track changes. Whilst improved, the manuscript still requires further minor revisions and another round of review. Thank you for the evaluation of our revised manuscript. We agree with most of the suggestions, which have been adjusted (for details see the manuscript with track changes). In brief, we changed the title, Figure 2 and most of the grammatical suggestions were incorporated. In addition we removed the term ‘systematic review’ in the whole manuscript, and clarified the terminology on reticulocyte counts and CRP/ESR. In addition the Footnotes for Tabel 2 and 3 are adjusted. Attachments Attachment Submitted filename: Response to reviewers.docx https://doi.org/10.1371/journal.pone.0333688.r004
18 Sep 2025 Decision Letter - Elizabeth Mayne, Editor Comparison of diagnostic algorithms used in guidelines on nutritional anaemias in adults PONE-D-25-00163R2 Dear Dr. De Jong, We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements. Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication. An invoice will be generated when your article is formally accepted. Please note, if your institution has a publishing partnership with PLOS and your article meets the relevant criteria, all or part of your publication costs will be covered. Please make sure your user information is up-to-date by logging into Editorial Manager at Editorial Manager® and clicking the ‘Update My Information' link at the top of the page. For questions related to billing, please contact billing support . If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org. Kind regards, Elizabeth S. Mayne, M.D. Academic Editor PLOS ONE Additional Editor Comments (optional): Reviewer #2: Reviewers' comments: Reviewer's Responses to Questions Comments to the Author 1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation. Reviewer #2: (No Response) ******** 2. Is the manuscript technically sound, and do the data support the conclusions? The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented. Reviewer #2: Yes ****** 3. Has the statistical analysis been performed appropriately and rigorously? Reviewer #2: N/A ****** 4. Have the authors made all data underlying the findings in their manuscript fully available? The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified. Reviewer #2: Yes ****** 5. Is the manuscript presented in an intelligible fashion and written in standard English? PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here. Reviewer #2: Yes ****** 6. Review Comments to the Author Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters) Reviewer #2: The corrections and comments have been addressed, and the article is now suitable for publication. ****** 7. PLOS authors have the option to publish the peer review history of their article (what does this mean? ). If published, this will include your full peer review and any attached files. If you choose “no”, your identity will remain anonymous but your review may still be made public. Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy . Reviewer #2: No ******** https://doi.org/10.1371/journal.pone.0333688.r005
Formally Accepted
Acceptance Letter - Elizabeth Mayne, Editor PONE-D-25-00163R2 PLOS ONE Dear Dr. De Jong, I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now being handed over to our production team. At this stage, our production department will prepare your paper for publication. This includes ensuring the following: * All references, tables, and figures are properly cited * All relevant supporting information is included in the manuscript submission, * There are no issues that prevent the paper from being properly typeset You will receive further instructions from the production team, including instructions on how to review your proof when it is ready. Please keep in mind that we are working through a large volume of accepted articles, so please give us a few days to review your paper and let you know the next and final steps. Lastly, if your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org. You will receive an invoice from PLOS for your publication fee after your manuscript has reached the completed accept phase. If you receive an email requesting payment before acceptance or for any other service, this may be a phishing scheme. Learn how to identify phishing emails and protect your accounts at https://explore.plos.org/phishing. If we can help with anything else, please email us at customercare@plos.org. Thank you for submitting your work to PLOS ONE and supporting open access. Kind regards, PLOS ONE Editorial Office Staff on behalf of Dr. Elizabeth S. Mayne Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0333688.r006

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